The UCLA clinical neurophysiology program project (CNP) is composed of tightly-coordinated, interactive, multi-disciplinary investigations into the fundamental mechanisms of human temporal lobe epilepsy by the collaborative efforts of a team for clinical and basic neuroscientists who have been working together for a number of years. The CNP is currently in its 38th year of NIH funding, and has continued to take advantage of the unique opportunities offered by an epilepsy surgery facility to carry out invasive research on patients with epilepsy. Emphasis was placed initially on clinical research, but by 1981 the program project became devoted entirely to basic research on normal and abnormal function of the human temporal lobe. Beginning with our last renewal, we further narrowed our focus to investigate only epileptic mechanisms of the hippocampus, particularly hippocampal sclerosis, and also began to include experimental animal models of human temporal lobe epilepsy. With this application, all subprojects integrate studies of temporal lobe epilepsy in patients, with parallel studies in the intra-hippocampal kainate rat model, which morphologically, electrophysiologically, and behaviorally resembles human mesial temporal lobe epilepsy with hippocampal sclerosis. Experimental protocols include in vivo electrophysiology and microdialysis, as ell as in vitro neurochemistry and molecular microanatomy, molecular and cellular physiology, and local circuit physiology, in patients and animals, with a particular emphasis on elucidating the role of the dentate gyrus in the epileptogenic properties of sclerotic hippocampus. We propose three subjects to investigate: i) molecular alterations in glutamate receptors on interneurons and their functional correlates; ii) changes in cellular excitability resulting from altered intracellular neurochemistry, neurotransmitter receptor function, and network characteristics; and iii) the neuroanatomical and neurochemical substrates of unique interictal and ictal epileptiform electrophysiological events recorded from the intact brain. We anticipate that elucidation of fundamental mechanisms underlying epileptic abnormalities of mesial temporal lobe epilepsy, the most common, and most refractory, form of human epilepsy, will ultimately result in new approaches to diagnosis, therapy and prevention of epilepsy, and its adverse biological consequences.